Collections > Electronic Theses and Dissertations > Challenging the Dogma: Reevaluating the Role of Astrocyte Calcium Signaling in Physiology

Gliotransmission represents one of the most important conceptual shifts in neuroscience in the past several decades. Gliotransmission refers to the process whereby glial cells release specific neurotransmitters that modulate synaptic transmission via pre- and postsynaptic activation of G-protein coupled (GPCR) and ionotropic receptors. Astrocytes release glutamate, ATP or D-serine upon activation of a wide range of Gq-GPCRs to modulate neuronal activity in the numerous regions of the brain. These "gliotransmitters" modulate spontaneous and evoked neuronal activity at both excitatory and inhibitory synapses, and affect heterosynaptic depression and long term potentiation in the hippocampus. The theory of astrocyte Ca2+-dependent modulation of neuronal activity is built upon the hypothesis that activation of Gq-GPCRs on astrocytes leads to Inositol trisphosphate (IP3) receptor-mediated calcium increases that trigger the release of gliotransmitters. However, evidence supporting this hypothesis has primarily relied on non-physiological methods for increasing or decreasing glial Ca2+. For example, uncaging of Ca2+ or chelation of intracellular Ca2+ in astrocytes affects synaptic transmission. However the usage of these methods does not specifically target IP3 receptor-mediated Ca2+ increases, considered the primary source of Ca2+ changes in astrocytes for gliotransmission. To probe the role of IP3 receptors (IP3R) in Ca2+-dependent release of gliotransmitters from astrocytes, we have used the IP3R type 2 (IP3R2) knockout mouse model. Through a combination of Ca2+ imaging and electrophysiology experiments we found that deletion of IP3R2 in astrocytes blocks intracellular Ca2+ increases in astrocytes in response to Gq GCPR activation. Further, that lack of IP3R-mediated Ca2+ increases does not affect excitatory synaptic transmission of both CA1 and CA3 pyramidal neurons in the hippocampus. Analysis of IP3R2 conditional knockout mice reveals specific behavioral changes in acoustic startle response and spatial learning in the Morris Water Maze. These novel findings represent a departure from the established theory of gliotransmission and are a significant step forward in our understanding of the role of astrocytic IP3R-mediated Ca2+ increases in physiology.